The material was carried to the next step without purification.
-(3-Hexyloxyphenoxy)-1-butanol (5). A 5-L, four-
necked, round-bottomed flask, equipped with a mechanical
stirrer, addition funnel, thermometer/temperature controller,
nitrogen inlet/outlet, condenser, and heating mantle, was
flushed with nitrogen for 10 min and charged with 120 g
sulfur, and the mixture was warmed to 20 °C over 30 min
and stirred for 16 h. The suspension was diluted with 500
mL of ethyl acetate, filtered through a polypropylene filter
pad, and rinsed with 100 mL of ethyl acetate. The filtrate
was diluted with 300 mL of heptane and cooled to 10 °C.
The mixture was stirred rapidly, and ∼1000 mL of 2 N
NaOH aqueous solution was added to adjust the pH of the
stirred suspension to 8. (The actual amount of base Varies.
It is important to bring the pH to the specified Value.) The
layers were separated, the lower aqueous layer was cooled
to 10 °C, and ∼130 mL of 6 N HCI aqueous solution was
added to adjust the pH to 2 (it is important to bring the pH
to the specified Value). Ethyl acetate (1 L) was added, the
mixture was stirred for 5 min, and the layers were separated.
The upper organic extract was cooled to -15 °C (external)
for 2.5 h; seed crystals were added to the solution. R-
Cellulose (67 g) was added to the suspension and stirred
vigorously for 15 min. The precipitate was filtered through
a polypropylene filter, and the filter cake was washed twice
with 20 mL of cold ethyl acetate (-10 °C). The filter cake
was transferered to a 3-L, three-necked flask, 120 mL of
ethanol was added, and the mixture was warmed to 60 °C.
The suspension was filtered through a polypropylene filter
pad; the cellulose residue was washed with an additional 400
mL of ethanol preheated to 50 °C, and again with 100 mL
of ethanol preheated to 50 °C. The combined filtrates were
concentrated under vacuum (40 °C, 60 mbar) to remove a
total of 900 mL of ethanol and stirred at 0 °C over a period
of 3.5 h. The suspension was filtered through a polypropylene
filter, and the filter cake was transferred the to a 3-L, three-
necked flask and dissolved in 800 mL of ethanol by heating
to 60 °C. The solution was cooled to 0 °C and stirred for 2
h, and the product was collected by filtration through a
polypropylene filter followed by washing with 25 mL of cold
ethanol (10 °C). The white solid was dried at 45 °C, 60 mbar
4
(
3.0 mol) of sodium hydroxide pellets, 0.5 L of deionized
water, 32.2 g (0.1 mol) of tetrabutylammonium bromide, and
14.0 g (0.75 mol) of 3-hexyloxyphenyl benzoate (containing
3
R-cellulose). The mixture was heated to 100 °C under
nitrogen, and 234.9 g (1.3 mol) of 10 was added over a period
of 1 h, heated at 100 °C for 5 h, and cooled to 50 °C. Heptane
(0.4 L) and 1.0 L of deionized water were added, and the
mixture was stirred at 25 °C for 15 min and filtered. The
cellulose residue was washed with 0. 1 L of heptane. The
layers were separated, and the organic layer was washed
twice with 0.5 L of deionized water. To the organic layer
were added 0.2 L of 6 N HCI solution and 100 mL of
deionized water, and the mixture was stirred vigorously at
25 °C for 1 h. The layers were separated, and the organic
layer was diluted with 0.4 L of heptane and 0. 1 L of ethyl
acetate, washed with 0.5 L of deionized water, and cooled
to -15 °C. After 2 h at -15 °C, the product was collected
by filtration. The filter cake was washed twice with 0.05 L
of cold heptane (∼-15 °C). The product was dried in a
vacuum oven (25 °C, 30 mbar) for 24 h to give 179.3 g of
2
(89.4% yield) as white, flaky crystals; mp 35.0-36.5 °C.
R,R)-3-Carboxy-2-[[[[4-[(3-hexyloxy)phenoxy]butoxy]-
(
mercapto]phosphinyl]oxy]-N,N,N-trimethyl-propanamin-
ium Inner Salt (1). A 5-L, four-necked, round-bottomed
flask, equipped with a mechanical stirrer, thermometer,
addition funnel, nitrogen inlet/outlet, and cooling bath was
charged with 200 mL of dry and peroxide-free THF and
cooled to -15 °C. PC1
over a period of 10 min, followed by a solution of 133 g
0.492 mol) of 2 in 300 mL of THF over a period of 30-40
3
(45.8 mL, 0.525 mol) was added
(
for 16 h to give 70.9 g of 1; (28% yield); mp 140.6-141.1
1
min, while maintaining an internal temperature of -15 °C.
The mixture was stirred at the same temperature for 10 min,
and 150 mL of tributylamine was added over a period of 30
min (very exothermic!) at -15 °C. An additional 327 mL
of tributylamine was added at the same temperature over 15
min. The reaction mixture was warmed to 3 °C over 10 min,
and a solution of 252.0 g (0.525 mol) of L-carnitine
tetraphenylborate salt dissolved in 500 mL of THF was added
over a period of 30 min, while maintaining the internal
temperature at 0 °C. The mixture was stirred at the same
temperature for 1 h. Deionized water (250 mL) was added
slowly over a period of 30 min at a temperature of 0-10
°C; H NMR (CD
3
OD) δ 0.92 (t, 3H, J ) 7.0 Hz), 1.27-
1.42 (m, 4H), 1.42-1.55 (m, 2H), 1.70-1.82 (m, 2H), 1.82-
1.95 (m, 4H), 2.70 (d,d, 1H, J ) 15.5, 9 Hz), 3.20 (d,d, 1H,
J ) 15.5, 2 Hz), 3.27 (s, 9H), 3.51-3.72 (m, 2H), 3.91-
4.15 (m, 6H), 5.16-5.30 (m, 1H), 6.42-6.53 (m, 3H), 7.13
1
3
(t, 1H); C NMR (CD OD) δ 14.41, 23.70, 26.91, 26.95,
3
28.19, 28.31, 32.44, 32.81, 39.57, 55.06, 66.84, 66.91, 68.20,
68.26, 68.58, 70.91, 102.59, 107.82, 107.85, 130.87, 161.78,
3
1
25
161.85, 173.91; P NMR (CD OD) δ 57.74; OR: [R]
3
-21.98° (c ) 0.95, MeOH).
Received for review May 28, 2003.
OP034064G
°
C. To the reaction mixture was added 77 g (2.4 mol) of
Vol. 7, No. 5, 2003 / Organic Process Research & Development
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